DE69827017T2 - COMBINATIONS OF ENDOMETRICALLY PROTECTED AND ENDOMETRICALLY ATROPHOSED AGENTS WITH ESTROGENIC IN ORAL CONCENTRATION PREVENTION - Google Patents

Abstract

An oral contraception regimen which comprises sequentially administering two or more progestational agents exhibiting different effects on the human endometrium in combination with an estrogen. The invention is also directed to an extended use oral contraception regimen comprising the sequential administration of two or more progestational agents in combination with an estrogen.

Description

Field of the invention

The The present invention relates to a plan of prescription Hormone combination for oral contraception in humans. Especially The present invention relates to a prescription plan for oral Contraception, which involves sequential administration of two or three several drugs with progestational action, the different Effects on the human endometrium in combination with an estrogen exercise, includes. The invention also relates to a prolonged use of the prescription plan for oral contraception, which involves sequential administration of two or more agents with progestational action in combination with an estrogen includes.

background the invention

formulations for oral contraception, which is a combination of a progestin and an estrogen are included, have been longer Time known. A series of different prescriptions to influence Ovulation and conception with these hormones is developed Service. conventional Regulation plans can a uniform dosage of either an estrogen or progestin or both during the entire administration period, or they can Amount of estrogen or progestin by elevating or decreasing the dosage during the administration period is used vary. For example, the US patents disclose Nos. 4,616,006 and 4,390,531 for oral Oral Triphasic prescription Contraception, taking the dosage of progestin in 3 sequences while of the 21-day Administration period is varied in an effort to reduce the side effects minimize and optimize contraceptive activity.

One Disadvantage of the present Regulation plans for oral contraception is the appearance of an abnormal intermenstrual bleeding or "breakthrough bleeding." In general For example, the targeted bleeding patterns of oral contraceptives are usually predictable and kick during 7-day drug-free Interval, which is based on a 21-day administration of the active ingredient follows. A "breakthrough bleeding" refers to the occurrence Bleeding or spotting during the 21-day administration period. It is reported that at approximately 20-30% Women a breakthrough bleeding or spotting occurs. Most frequently occurs a breakthrough bleeding during the first few months of treatment and appears with the dose and the type of hormonal components as well as the idiosyncratic ones To relate answers. Another related problem related to traditional Regulation plans for oral contraception is the occurrence of an early withdrawal flow, which is any bleeding or spotting during the Interval of drug administration is, without interruption extends into the period in which the drug administration is discontinued. Because the interruption of a method of contraception due to an abnormal intermenstrual bleeding continues to be an important Factor is the interruption of drug intake and unwanted Pregnancy leads, there is a need for combined formulations for oral contraception, which the different clinical requirements of the user Fulfills and which makes the most acceptable bleeding pattern available.

Prescriptions on the extension Application has been studied using oral contraceptives for up to 3 months between cycles. A 3-month study to regulations for oral contraceptives, which reduce the menstrual rate was first tested by Loudon, NB, Br. Med. J. 1977; 2: 487-90 described. The advantages of such regulations are that she provide freedom from menstrual flow and premenstrual symptoms for extended periods of time and are generally easier to follow. Such ordinances extended to Application also find application in case of dismenorrhea, menorrhagia, symptoms of premenstrual Type or menstrual migraine. Sulalc et al., Obstet. Gynecol. 1997; 89: 179-83 report in a retrospective Analysis that 74% Patients who were continuously drug-containing for 6 weeks Pills were treated, stabilized, and that the prescription plan to the extended one Application of oral contraceptives delayed the onset and severity of reported Complaints weakened. However, such regulations are extended for prolonged use frequent Occurrence of a breakthrough bleeding impaired, which is a common cause interruption of the regulation.

Accordingly, there is a need for a regimen for the treatment of oral contraceptives that reduces the incidence of bleeding abnormalities. As will be shown, there is also a related need for a regimen of oral contraceptive regimens that will facilitate this reduction in the incidence of Occurrence of bleeding abnormalities while the treatment has a beneficial effect on the morphology of the endometrium.

It There is also a need for a prescription plan for treatment with oral contraceptives over one extended Period of application, which achieves effective contraception, during the however, there is a reduced incidence of bleeding abnormalities.

Various Progestins in oral combination contraceptives seem to be different Associated with bleeding patterns. While the mechanism of bleeding irregularities still little the applicants of the present invention have various Pattern of breakthrough bleeding and spotting in comparative Studies on the oral combination contraceptives norgestimate / ethinylestradiol observed in comparison to levonorgestrel / ethinylestradiol. The Variation of bleeding patterns was among those patients who while of the cycles before the study, no oral contraceptives were taken had, stronger pronounced. In general, the overall rate of episodes was similar to breakthrough bleeding, the Patterns differed, however.

drugs with progestational effects also differ in their effects on the endometrium. This can be from a proliferative or secretory Endometrium to a non-vascular or atrophic condition, which resembles the histological structure in the postmenopausal period. These effects are manifested by morphological changes the endometrial glands, spiral capillaries, endometrial stromal and epithelial tissues. A cycle control during The use of oral contraceptives is consistent with the maturity patterns of Related to endometrium. Depending on the active ingredient used with progestagen effect one can therefore histological differences prove between preparations, the following can influence the bleeding patterns. It has been observed that the morphological Appearance of the endometrium differs for norgestimate and levonorgestrel formulations is. After a 6-month Treatment with norgesimate / ethinyl estradiol was a well-preserved Epithelial lining observed, the midcycle or the early secretory Phase of the normal menstrual cycle corresponded. (Rabe, T. et al., Gerburtsh. Frauenheilk. 1986, 46: 883). It turned out that in primates Norgestimate one, the endometrium-sparing effect in comparison to other progestins (Wilborn, WH et al., 1984, 4th Annual Meeting of Ala. Academy of Science, Tuscaloosa, Ala.). In general show the findings during treatment in humans with norgestimate-containing oral contraceptives a secretory transformation to well-developed endometrium, for the however, it was proved that it is unable to carry an implanted blastocyst. in the In contrast, women who use levonogestrel-containing oral contraceptives were treated, generally the appearance an atrophic endometrium with reduced gland diameter and glandular epithelium.

Summary the invention

• (a) 7–14 Tageseinzeldosen eines, das Endometrium schonenden Progestins (ESP) in Kombination mit einem Östrogen; und
• (b) 7–14 Tageseinzeldosen eines atrophisch wirkenden Progestins (AP) in Kombination mit einem Östrogen;

wobei die Tageseinzeldosen zur sequentiellen Verabreichung angeordnet sind.In accordance with the present invention, there is provided a pharmaceutical pack containing:

• (a) 7-14 daily single doses of an endometrial-sparing progestin (ESP) in combination with an estrogen; and
• (b) 7-14 daily single doses of an atrophic progestin (AP) in combination with an estrogen;

wherein the daily single doses are arranged for sequential administration.

The The present invention also provides a pharmaceutical package which Single daily doses for an extended one Application period of three months contains, alternating in first and second groups are arranged, each first group containing 7-14 ESP-containing Contains daily doses, and every other group 7-14 Contains AP-containing daily doses.

Precise description the invention

In accordance with the present invention, a prescription plan for an oral combination contraceptive is provided with progestin which utilizes alternating an endometrial-sparing progestin with an atrophic progestin at intervals that can alter the morphology of the endometrium thereby reducing bleed bleeding by: both irregular rejection of atrophied endometrium and termination of very glandular endothelium in the later stages of continued stimulation is reduced. By maintaining a balance between these two effects in sequential phases, the prescription plan allows extended intervals between withdrawal bleeding.

Of the Term "the Endometrium-sparing progestin " every compound that has progestational activity and that has a secretory one Morphology of the endometrium with a well-preserved glandular structure induced. Examples of endometrial-sparing progestins are norgestimate and norethindrone.

As As used herein, the term "atrophic progestin" refers to any compound, the progestational activity and that has a morphology of an atrophic endometrium with reduced gland diameter and glandular epithelium induced. Examples of atrophic progestins are desogestrel, Gestroden and levonorgestrel.

As found that the applicants have observed various types of bleeding, that are related to various progestins. In a Randomized comparative study on norgestimate / ethinylestradiol (NGM / EE 250/35) versus levonorgestrel / ethinylestradiol (LNG / EE 150/30) were various patterns of breakthrough bleeding and spotting observed. In general, the overall rates of bleeding episodes were similar, however, the patterns differed (that is, when in the cycle the Episode occurred). From this observation, which are the different Bleeding pattern, and the knowledge of the different Morphology of the endometrium with the different progestins related, use is made, therefore, a method for reducing the occurrence a breakthrough bleeding obtained by the application of progestins, which these different characteristics in the sense of this invention show, be combined.

According to the present Invention is the composition of the oral combination contraceptive with progestin over administered for a period of 21 to 90 days. This is followed Period of 6 to 8 days while of which the hormones are discontinued to normal menstruation to allow. Day 1 of the cycle is defined as the first day of the cycle Administration. The days are then numbered sequentially until the hormone is discontinued and menstruation occurs. A placebo or another hormone-free drug, such as an iron supplement, can while the withdrawal phase are administered.

The Composition of the combination contraceptive with progestin present invention 21-90 single dosage units used for administration of single daily dosages are provided. The composition consists essentially of a first phase with 7-14 Dosage units, the atrophically acting progestin in combination with an estrogen in admixture with a pharmaceutically acceptable carrier, one second phase with 7-14 Dosage units containing a, the endometrium-sparing progestin in combination with an estrogen and a pharmaceutically acceptable carrier contains and optionally additional Phases with alternately atrophic progestin and the endometrium gentle progestin in combination with an estrogen for a total period of 21-90 Days. The composition may optionally be 6-8 day single doses of hormone-free units included. The dosage and the type of estrogen component are generally during throughout the cycle, while the type of progestin remains constant alternately sequentially. The dosage of progestin in each phase can also be varied, if necessary, to a maximum To achieve effect.

It can any conventional estrogen as the estrogen component of the oral combination contraceptive of the present invention be used. Preferably, the estrogen component is in a Daily dosage equivalent of about 0.020 to 0.050 mg of ethinyl estradiol, preferably in an equivalent of about 0.030 mg ethinyl estradiol used.

The progestin component is preferably administered at a daily dosage equivalent to a progestational activity of 0.065-2.0 mg of norethindrone per day. The dosage of the progestin component may also be varied in biphasic or triphasic sequences to allow less progestin to be administered at an early stage of administration with increasing dosages used in the later stages of administration. For example, a biphasic dosage may be used wherein the dosage of an endometrial-sparing progestin administered in the first phase of administration may correspond to a progestational activity of 0.065-0.75 mg norethindrone per day while the dosage of an atrophic Progestins administered in the second stage is in the range of a progestational activity of 0.25-2.0 mg norethindrone per day. Similarly, the dosage of progestin may be in a triphasic manner as in US Pat. Nos. 4,616,006 and 4,390,531 be put. It may also be desirable to administer only the estrogen component for the first 1 to 7 days of administration, followed by the onset of menstruation as disclosed in U.S. Patents 4,921,843 and 5,280,023.

Of the Ordinance for a combination with progestin of the present invention is particularly useful for a continuous Therapy with a 3-month prolonged use, whereby the Hormones continuously over a period of up to three months before being administered administration is discontinued and withdrawal bleeding occurs. It is being considered pulled that one such treatment plan alternates the administration of the, the endometrium gentle progestin with the atrophic acting Progestin during of the 3-month administration period. For example would the combination from the endometrium-sparing progestin / estrogen for a period of about 7-14 days followed by administration of the combination of atrophic progestin / estrogen for one Period of about 7-14 days follows. The two progestin / estrogen combinations would then in an order during of the 3-month extended Administration period, followed by a one-week interval with a withdrawal flow follows.

It is assumed by alternating application of the two progestins, the different Exert effects on the endometrium, the occurrence of intermenstrual Bleeding would be reduced what the application of the extended Regulation with a minimum of adverse effects.

The dosages described are generally preferred but may be Of course adjusted to the optimal therapeutic response available make, what of the needs the patient, weight and age of the patient, special Hormone combination composition used, and the relative effectiveness of the active ingredients involved. The Determination of optimal dosages in a specific situation in the field of expertise in the medical field.

According to the present Invention, the estrogen and progestin active ingredients preferably together orally with a pharmaceutically acceptable carrier administered. In general, you can the active ingredients combined with one or more pharmaceutically acceptable carriers be used, for example, solvents, diluents and such, and can orally in such forms as tablets, capsules, dispersible Powders, granules or suspensions, for example, about 0.05-5% of a suspending Active ingredient, syrups, for example, about 10 to approximately Containing 50% sugar, and elixirs, for example, about 20-50% ethanol contained, and such together with the usual additives or auxiliaries in accordance with generally accepted be administered pharmaceutical practice. Such pharmaceutical preparations can for example about 0.5 up to about 90% of the active ingredient in combination with the carrier, usually between approximately 5 and 60 wt .-% included. While the estrogen and progestin components, preferably for oral administration can be combined the estrogen and progestin components also administered separately or parenterally become.

Of the carrier can be represented by one or more substances that as diluents, flavorings, Solvent, Lubricant, suspending agent, binder or disintegrating agent as well how encapsulating materials work. Suitable solid carriers include starch, lactose, Dicalcium phosphate, microcrystalline cellulose, sucrose, talc, Magnesium carbonate, kaolin and such. Suitable liquid carriers include sterile ones Water, polyethylene glycol, nonionic surfactant Agents and edible oils, such as peanut and sesame oils, as the nature of the active ingredient and the specific Shape of the desired Administration is appropriate. Adjuvants, usually at the time of preparation Pharmaceutical compositions can be used advantageously such as flavorings, colors, preservatives and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.

The active agents can also by other means known in the art, the used in the pharmaceutical field. For example, you can the estrogen and progestin alone or in combination for transdermal administration by means of a dermal patch, for administration by intramuscular injection, contained in an inert matrix implanted in the body in the form of a depot becomes, or intravaginally in a matrix, slowly the active ones Compositions releases, be formulated.

The active compounds may also be administered parenterally. Solutions or suspensions The active ingredients may be prepared in water suitably mixed with a surface active agent such as hydroxypropyl cellulose. Dispersions can also be made in glycerin, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The Pharmaceutical compositions are preferably in the form a pharmaceutical kit or a pharmaceutical pack Packaged, the daily dosages for a proper sequential Administration are arranged. This invention therefore relates also a pharmaceutical pack containing the combination of active estrogen and progestin agents in individual dosage units in contains a synchronized, fixed order, where the order the prescription plan of an oral contraceptive of the present invention.

For example For example, the pharmaceutical pack may be in the form of a kit which contains individual tablets, which are arranged sequentially, and consisting of 7-14 daily single doses of, the Endometrium-sparing progestins in combination with the estrogen, followed by 7-14 Single daily doses of atrophic progestin in combination with the estrogen consists. This order of tablets may vary 21-90 Alternate tablets. After all can optionally to the tablets containing the active ingredient to add 7 placebo tablets, to continuously administer one tablet daily.

Of the Regulation plan of the present invention can be characterized by the following Examples are better understood, but these are not limiting should.

EXAMPLE 1

Ordinance on the Uniphasic dosage

EE

Ethinylestradiol

NGM

Norgestimat

LNG

Levonorgestrel

On day 1 through day 10, 0.035 mg of ethinylestradiol with 0.250 norgestimate are administered daily. From day 11 through day 21, 0.035 mg ethinylestradiol with 0.150 mg levonorgestrel is administered daily. From day 22 through 28, placebo is administered, during which time menstruation occurs. The ordinance plan is shown in Table I. TABLE I

EE

ethinylestradiol

NGM

norgestimate

LNG

levonorgestrel

EXAMPLE 2

Ordinance on the biphasic dosage

One The biphasic dosing regimen will be published in accordance with the following table II.

TABLE II

EXAMPLE 3

Ordinance on the Triphasian dosage

One The ordinance for the triphasic dosage will be published in accordance with the applied to the following Table III.

TABLE III

EXAMPLE 4

Ordinance on the extended 3-month application

One Ordinance on the extended 3-month use will be carried out in accordance with the applied in the following Table IV.

TABLE IV

Claims (14)

A pharmaceutical pack comprising: a. 7 to 14 daily single doses of a, the endometrium-sparing progestin (ESP) in combination with an estrogen; and b. 7 to 14 daily single doses of an atrophic acting Progestins (AP) in combination with an estrogen; the daily single doses arranged for sequential administration. A package according to claim 1, wherein: the ESP Norgestimate or norethindrone is; the AP desogestrel, gestodene or levonorgestrel is; and the estrogen Ethinylestradiol, mestranol or 17-β-estradiol. A package according to claim 1 or 2, wherein: each ESP-containing daily dose contains 0.065 to 2.0 mg norethindrone; each AP-containing daily dose contains 0.050 to 0.250 mg levonorgestrel; and each Daily dose (1.020 to 0.050 mg ethinylestradiol contains. A package according to any one of claims 1 to 3, wherein in total 21 daily doses of ESP-containing and AP-containing cans arranged in 2 consecutive groups are. A package according to claim 4, wherein it contains 10 ESP-containing Daily doses in the first group and 11 AP-containing daily doses in the second group there. A package according to claim 1, wherein: every daily dose the same amount of estrogen contains; and each ESP-containing dose is the same relative amount Contains ESP as the amount containing each AP-containing dose of AP in. A package according to claim 6, wherein each ESP-containing Daily dose contains 0.035 mg ethinyl estradiol and 0.250 mg norgestimate and each AP-containing daily dose 0.035 mg ethinylestradiol and 0.150 mg levonorgestrel contains. A package according to claim 4, wherein each daily dose is the same amount of estrogen contains and each ESP-containing dose is a lower relative amount Contains ESP as the amount containing each AP-containing daily dose of AP. A package according to claim 8, wherein each ESP-containing Daily dose contains 0.035 mg ethinyl estradiol and 0.180 mg norgestimate and each AP-containing daily dose 0.035 mg ethinylestradiol and 0.150 mg levonorgestrel contains. A package according to claim 1, wherein: a first Group of daily progestin doses, a second group of progestin daily doses and one third group of progestin daily doses for sequential administration are arranged; each daily dose the same amount of estrogen contains; each Progestin-containing daily dose in the first group a lower contains relative amount of progestin as the amount containing each progestin-containing dose in the second Contains group of progestin; and each progestin-containing dose in the second group contains a lower relative amount of progestin than the amount each Progestin-containing daily dose in the third group of progestin contains. A package according to claim 10, wherein: the first Group contains 7 daily doses, each containing 0.035 mg of ethinylestradiol and 0.180 mg of norgestimate; the second group contains 7 daily doses, each containing 0.035 mg of ethinylestradiol and 0.215 mg of norgestimate; and the third group contains 7 daily doses, each containing 0.035 mg ethinylestradiol and 0.150 mg levonorgestrel. A package according to any one of claims 1 to 11, which is a group from 6 to 8 placebo daily doses in connection to includes the ESP-containing and AP-containing doses. Pharmaceutical pack, the daily single doses for one extended Usage period of 3 months, which alternately in first and second groups are arranged; in which every first group Contains 7 to 14 daily doses containing ESP; and every second group Contains 7 to 14 daily doses containing AP. A package according to claim 13 which comprises a group of 6 to 8 placebo daily doses following all includes alternating groups of ESP-containing and AP-containing daily doses.